Cystic Fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is the most common significant complication of CF and is associated with increased morbidity and mortality. CFRD, which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly worsens the nutritional and pulmonary health of CF patients. Glycemic abnormalities are common in children with CF, and the 13% of CF children 6-10 years of age that have abnormal glycemic status are at extraordinarily high risk for developing diabetes within the next few years. Our studies in CF ferrets and children 3 months to 5 years of age suggest that the underpinnings of CFRD occur very early in life. Of 12 CF subjects who were 1-5 years of age and have at least one ?F508 allele, 42% demonstrated abnormal glucose tolerance. This high incidence of abnormal glucose tolerance in young CF children as compared to slightly older children (13% at 6-10 years of age) is consistent with our discovery that in CF ferrets glucose intolerance develops in phases (with intervening periods of temporary recovery) that are associated with changes in the regulation of insular axis hormones and fibrotic remodeling of the pancreas. A major goal of this R24 is to identify the early pathophysiologic events involved in CF pancreas remodeling and the development of CFRD. The observed disturbances in insular and entero-insular axis hormones in young CF children are consistent with the hypothesis that both positive and negative adaptive changes influence insulin regulation, and potentially insulin action. Similar age-dependent alterations occur in CF ferrets and will enable us to dissect the mechanisms that underlie these processes. Studies in isolated human, ferret, and pig islets have demonstrated that CFTR impacts glucose-stimulated insulin secretion by islets through its activity in either endocrine cells or islet-associated ductal cells. The propose research will identify pancreas-intrinsic and -extrinsic events that alter insulin secretion and glycemic status in CF, with a focus on defining (i) the islet-intrinsic mechanisms that control CFTR-dependent insulin secretion in vitro and in vivo, (ii) the pancreas-extrinsic mechanisms that lead to abnormal insulin secretion and altered glucose physiology in CF, and (iii) the extent to which endocrine pancreas remodeling contributes to subsequent abnormalities in insulin secretion, and whether amelioration of the primary wave of pancreas inflammation in CF can prevent maladaptive islet remodeling. These studies are expected to identify early blood biomarkers of CFRD risk, as well as methods for early intervention.